The use of hydroxypropylmethyl cellulose as a rate controlling hydrophilic polymer in controlled release formulations is well-documented.
A major problem associated with most existing controlled release systems containing hydroxypropylmethyl cellulose and other pH independent rate controlling polymers is that they provide no control over drug release into media of differing pH, where drug solubility is dependent upon pH.
During transit down the digestive tract different pH environments are encountered. In the stomach acidic conditions are predominant. A gradual increase in pH then occurs during transit down the small intestine. These variations are complicated by the influence of food. For example, in the fasted state the stomach is more acidic than after a meal. Consequently this may influence the release behavior of a product which is not pH independent in its performance.
In addition, variable gastric emptying times may affect dosage form performance. A drug with an absorption "window" or poor bioavailability from the lower regions of the digestive tract may not achieve an extended period of absorption. For a drug absorbed primarily in the upper small intestine rapid gastric emptying may result in an absorption spike with no prolonged pharmacokinetic profile. Similarly with poor absorption from the large intestine rapid dosage form transit will shorten the effective period of drug delivery from the formulation. To achieve the optimum extended delivery characteristics it is therefore desirable to combine retention in the stomach with additional pH independent release. This maximizes time of drug availability for absorption and ensures consistent release regardless of elapsed time or position in the intestine.
Alginate based systems have been proposed as oral sustained release matrix dose forms. Gel formation in these systems is governed by an interaction between calcium ions and alginic acid. "Gel Formation with Alginate", Data Sheet D1571, Alginate Industries Limited, London, discloses that "gel formation is obtained by steady and uniform release of calcium, or other cations capable of forming an insoluble alginate, into the alginate solution". Other workers (Stockwell, A. F. et al., Journal Controlled Release, 3 (1986) 167-175) have employed the calcium gelled alginate system in combination with CO.sub.2 generating excipients to yield a tablet that floats on the gastric contents. Such systems are not intended to pass down the GI tract and release drug in variable pH environments.
Howard et al. U.S. Pat. No. 4,792,452 discloses a non-buoyant controlled release pharmaceutical formulation in the form of a tablet which includes a basic pharmaceutical, up to about 45% by weight of a pH dependent polymer which is a salt of alginic acid, such as sodium alginate, up to about 35% by weight of a pH independent hydrocarbon gelling agent, binder and excipients. In column 3, lines 45 to 48, Howard et al. indicate that their controlled release formulation will not float in the stomach since it is more dense than water.
The use of hydrocolloid gelling agents in floating sustained release tablet formulations is known in the art. For example, Bolton et al. U.S. Pat. No(s). 4,814,178 and 4,814,179 each disclose tablets which float in gastric fluid and which contain a hydrocolloid gelling agent, a therapeutic agent and water and in the case of U.S. Pat. No. 4,814,179, an inert oil as well.
Sheth et al. U.S. Pat. No(s). 4,140,755 and 4,167,558 each disclose tablets which are buoyant in gastric juice and contain one or more hydrophillic hydrocolloids which in contact with gastric fluid will form a gelatinous mass on the surface of the tablet, thus causing it to enlarge and acquire a bulk density of less than one. However, this provides for no control of release under different pH conditions, thus drug dissolution rate will vary according to the duration of time spent in the stomach.
Umezawa U.S. Pat. No. 4,101,650 discloses pepstatin floating minicapsules wherein pepstatin is coated on very small granules of sodium bicarbonate.
Ushimaru et al. U.S. Pat. No. 4,702,918 discloses a sustained release composition which includes a gel-forming substance such as a cellulose derivative like hydroxypropylmethyl cellulose, a polysaccharide-like alginic acid, a starch derivative, a dextran, a polypeptide, a protein, or acrylic acid or vinyl derivative, together with a fat/oil which is solid at room temperature and a pharmaceutical. The sustained release composition may be in the form of a powder-filled capsule.
Stockwell et al., J. Controlled Release, 3, 167-175 (1986), investigated alginate gel formulations which included sodium bicarbonate, the intention being that the release of carbon dioxide which occurred on contact of the formulation with gastric fluid would become entrapped in the gel network producing a buoyant system. The concept was carried further by Ingani et al., Int. J. Pharm., 35, 157-164 (1987) who produced tableted and floating dosage forms of a riboflavin derivative and compared their bioavailability in vivo. It was found that the bioavailability of the floating dosage forms was increased compared to the standard system. This was considered in-direct evidence that gastric retention times were increased for the novel preparation.
Various in vivo studies have been performed using these dosage forms in order to verify the possible effects of device density upon gastric retention times. The results obtained from the various studies draw conflicting conclusions; it is likely that the effectiveness of the intragastric buoyancy process may be dependent on the particular physiological conditions and/or on the dosage form characteristics. J. Timmermans, A. J. Moes, Int. J. Pharm., 62, 207-216 (1990).